Synthesis and Bioactivity Evaluation of KDM4 Inhibitors in Prostate Cancer Cells

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dc.contributor.advisorAhn, Jung Mo
dc.contributor.advisorPenev, Kaloyan
dc.contributor.committeeMemberSmaldone, Ronald A.
dc.contributor.committeeMemberD'Arcy, Sheena
dc.contributor.committeeMemberStefan, Mihaela C.
dc.creatorSmith, Tristan
dc.date.accessioned2024-03-13T16:05:57Z
dc.date.available2024-03-13T16:05:57Z
dc.date.created2022-12
dc.date.issuedDecember 2022
dc.date.submittedDecember 2022
dc.date.updated2024-03-13T16:05:57Z
dc.description.abstractThe need for alternative therapeutic targets has grown due to the stagnating progress of treatment for metastatic prostate cancer with activity independent of the androgen receptor. Inhibition of histone lysine demethylases belonging to the KDM4 subfamily are of significant interest due to their aberrant expression and role in castration-resistant prostate cancer. This dissertation presents the design, synthesis, and biochemical evaluation for a library of 8-hydroxyquinoline-based derivatives of B3, a KDM4 inhibitor that has previously demonstrated therapeutic potential. Motivated by the search for improved efficacy for KDM4 inhibition in prostate cancer, the first investigation highlights the structure-activity relationship discovered from modifying the phenylpropyl moiety of B3. Screening a comprehensive list of different chemical groups revealed several with improved inhibitor activity and stability. Continuing our search for improved efficacy, the second investigation explored augmentation of the benzamide moiety of B3 that led to the identification of a new lead inhibitor using 4-(3-methoxypropyl)morpholine. This modification to B3 led to the desired cytotoxicity to tumor viability during in vitro MTT assays and in vivo murine studies.
dc.format.mimetypeapplication/pdf
dc.identifier.uri
dc.identifier.urihttps://hdl.handle.net/10735.1/10039
dc.language.isoen
dc.subjectChemistry, Pharmaceutical
dc.subjectChemistry, Biochemistry
dc.subjectBiology, Cell
dc.titleSynthesis and Bioactivity Evaluation of KDM4 Inhibitors in Prostate Cancer Cells
dc.typeThesis
dc.type.materialtext
local.embargo.lift2023-12-01
local.embargo.terms2023-12-01
thesis.degree.collegeSchool of Natural Sciences and Mathematics
thesis.degree.departmentChemistry
thesis.degree.grantorThe University of Texas at Dallas
thesis.degree.namePHD

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